Ziapin2 effectively restores retinal function in preclinical models of retinitis pigmentosa and macular degeneration

A multidisciplinary team of researchers from the Istituto Italiano di Tecnologia (IIT-Italian Institute of Technology) and IRCCS Ospedale Policlinico San Martino has demonstrated the effectiveness of the Ziapin2 molecule as a promising new instrument in countering the effects of retinitis pigmentosa and age-related macular degeneration, conditions that lead to the progressive deterioration of the photoreceptors in the retina, causing progressive blindness.

The findings are published in the journal Nature Communications.

The team was coordinated by Fabio Benfenati, head of the Center for Synaptic Neuroscience and Technology at IIT, and Stefano Di Marco, in collaboration with the Politecnico di Milano.

Retinitis pigmentosa is a relatively rare genetic disorder (affecting 1 in 3,500 people), while age-related macular degeneration affects 7–8% of the population, and its incidence increases with age.

There are currently no effective treatments for restoring sight in cases of retinitis pigmentosa and macular degeneration, and the methods applied by the scientific community based on substituting the process of phototransduction of deteriorated photoreceptors, such as optogenetics and retinal prostheses, have led to partial results in restoring sight, above all due to the indistinct activation of retinal neurons, independent of separation of visual information regarding light and dark in the ON and OFF channels, which plays an essential role in sensitivity to contrast and spatial resolution.

The study demonstrates that by modifying—in a light-dependent manner—the electrical properties of the neuronal membrane in response to light, the molecule Ziapin2 can restore ON, OFF and ON-OFF responses induced by light stimuli in the retina in pre-clinical models of retinitis pigmentosa, with the consequential reactivation of multiple response types typically present in healthy retinas.

Furthermore, when injected intravitreally into pre-clinical models of retinitis pigmentosa that had reached a state of complete blindness, Ziapin2 demonstrated its ability to restore light-induced behavior and visual acuteness, with an effect lasting for two weeks, passing all biocompatibility tests.

The Ziapin2 molecule was first patented in 2020 by Chiara Bertarelli, Guglielmo Lanzani e Fabio Lanzani and presented in the journal Nature Nanotechnology. Ziapin2 is a phototransducer that absorbs light and transforms it into an electrical signal; by entering the neuronal membrane, it modulates the excitability of the neurons in accordance with light, acting exclusively on the passive properties of the membrane without interfering with ion channels or neurotransmitter receptors.

In their last study, IIT’s research group saw for the first time that Ziapin2 also acts in a similar manner on neurons in the inner retina unaffected by degeneration, particularly at the bipolar-cell level, where light/dark information is segregated into distinct ON and OFF channels and then sent by the ganglion cells to the brain via the optical nerve.

In comparison to previous results obtained on cellular models, this research confirms the effectiveness of the molecule in an in-vivo context, paving the way for possible developments with a view to future clinical applications.

“The results obtained show that the Ziapin2 molecule is extremely promising for restoring visual response in cases of photoreceptor degeneration,” stated Fabio Benfenati, coordinator of the Center for Synaptic Neuroscience and Technology at IIT and researcher at IRCSS San Martino Hospital in Genova.

“We have been able to demonstrate that Ziapin2 can regenerate the physiological antagonism between the ON retinal neurons, which signal the presence of light, and the OFF neurons, which signal the absence of light at the bipolar cellular level of the retina. The restoration of differential activity is fundamental for complex retinal response to light stimulation, which allows for more natural vision.”

“In pre-clinical models of retinitis pigmentosa, Ziapin2 restored response to light and contrast for up to two weeks following a single intravitreal injection, without any toxic or inflammatory effects,” concluded Stefano Di Marco, an affiliate IIT researcher and currently Professor at University in Genova. “This innovative approach could represent a turning point in recovery of sight in the field of degenerative retinal diseases.”

“Ziapin2 proves to be a key molecule in acting exclusively on the passive properties of the membrane,” declares Chiara Bertarelli, Professor at the Politecnico di Milano. “This study highlights its in vivo efficacy and potential applications.”

A multidisciplinary team of researchers from the Istituto Italiano di Tecnologia (IIT-Italian Institute of Technology) and IRCCS Ospedale Policlinico San Martino has demonstrated the effectiveness of the Ziapin2 molecule as a promising new instrument in countering the effects of retinitis pigmentosa and age-related macular degeneration, conditions that lead to the progressive deterioration of the photoreceptors in the retina, causing progressive blindness.

The findings are published in the journal Nature Communications.

The team was coordinated by Fabio Benfenati, head of the Center for Synaptic Neuroscience and Technology at IIT, and Stefano Di Marco, in collaboration with the Politecnico di Milano.

Retinitis pigmentosa is a relatively rare genetic disorder (affecting 1 in 3,500 people), while age-related macular degeneration affects 7–8% of the population, and its incidence increases with age.

There are currently no effective treatments for restoring sight in cases of retinitis pigmentosa and macular degeneration, and the methods applied by the scientific community based on substituting the process of phototransduction of deteriorated photoreceptors, such as optogenetics and retinal prostheses, have led to partial results in restoring sight, above all due to the indistinct activation of retinal neurons, independent of separation of visual information regarding light and dark in the ON and OFF channels, which plays an essential role in sensitivity to contrast and spatial resolution.

The study demonstrates that by modifying—in a light-dependent manner—the electrical properties of the neuronal membrane in response to light, the molecule Ziapin2 can restore ON, OFF and ON-OFF responses induced by light stimuli in the retina in pre-clinical models of retinitis pigmentosa, with the consequential reactivation of multiple response types typically present in healthy retinas.

Furthermore, when injected intravitreally into pre-clinical models of retinitis pigmentosa that had reached a state of complete blindness, Ziapin2 demonstrated its ability to restore light-induced behavior and visual acuteness, with an effect lasting for two weeks, passing all biocompatibility tests.

The Ziapin2 molecule was first patented in 2020 by Chiara Bertarelli, Guglielmo Lanzani e Fabio Lanzani and presented in the journal Nature Nanotechnology. Ziapin2 is a phototransducer that absorbs light and transforms it into an electrical signal; by entering the neuronal membrane, it modulates the excitability of the neurons in accordance with light, acting exclusively on the passive properties of the membrane without interfering with ion channels or neurotransmitter receptors.

In their last study, IIT’s research group saw for the first time that Ziapin2 also acts in a similar manner on neurons in the inner retina unaffected by degeneration, particularly at the bipolar-cell level, where light/dark information is segregated into distinct ON and OFF channels and then sent by the ganglion cells to the brain via the optical nerve.

In comparison to previous results obtained on cellular models, this research confirms the effectiveness of the molecule in an in-vivo context, paving the way for possible developments with a view to future clinical applications.

“The results obtained show that the Ziapin2 molecule is extremely promising for restoring visual response in cases of photoreceptor degeneration,” stated Fabio Benfenati, coordinator of the Center for Synaptic Neuroscience and Technology at IIT and researcher at IRCSS San Martino Hospital in Genova.

“We have been able to demonstrate that Ziapin2 can regenerate the physiological antagonism between the ON retinal neurons, which signal the presence of light, and the OFF neurons, which signal the absence of light at the bipolar cellular level of the retina. The restoration of differential activity is fundamental for complex retinal response to light stimulation, which allows for more natural vision.”

“In pre-clinical models of retinitis pigmentosa, Ziapin2 restored response to light and contrast for up to two weeks following a single intravitreal injection, without any toxic or inflammatory effects,” concluded Stefano Di Marco, an affiliate IIT researcher and currently Professor at University in Genova. “This innovative approach could represent a turning point in recovery of sight in the field of degenerative retinal diseases.”

“Ziapin2 proves to be a key molecule in acting exclusively on the passive properties of the membrane,” declares Chiara Bertarelli, Professor at the Politecnico di Milano. “This study highlights its in vivo efficacy and potential applications.”